In this grant we propose to study the airway responses to endotoxemia in the unanesthetized sheep while simultaneously measuring changes in the pulmonary vasculature, lung lymph, and lung fluid balance. This preparation serves as a useful animal model of the adult respiratory distress syndrome in man following gram-negative endotoxemia. The changes observed in the sheep, including changes in the airways, vasculature, and fluid balance, mimic those seen in man. The airway changes are not explained solely by fluid accumulation since marked alterations occur in airway mechanics and oxygenation before there is any evidence of pulmonary edema or increased microvascular permeability. We propose to study the mechanisms through which endotoxin affects the airways. We propose to carefully study the relationship of airway changes to changes in the vasculature and fluid balance; to study the possible role of products of arachidonate metabolism and histamine in causing these changes; to study whether vagal reflexes or circulating granulocytes play a role in mediating the airway responses and to study changes in tissue, lymph, and blood levels of cyclic nucleotides, histamine, and arachidonate metabolites in relationship to the observed changes in the airways and vasculature. We propose further to study the recovery of the sheep from endotoxemia in terms of pulmonary mechanics and airway reactivity since residual alterations have been described in man. Further, we will try to discover what mechanisms are responsible for any residual changes.